Exploring Vacuum Compression Molding as a Preparation Method for Flexible-Dose Pediatric Orodispersible Films

Introduction

The recent initiatives of the regulatory authorities provide a dynamic landscape for pediatric medicines, encouraging the development of high-quality and innovative formulations at affordable costs. The importance of research on novel delivery systems and formulation approaches for pediatric medicines is therefore emphasized [1,2]. Yet, these objectives pose financial challenges for the pharmaceutical industry due to the necessity to develop formulations with distinct characteristics for specific age groups, such as neonates, infants, children, or adolescents [3]. Moreover, the scarcity of data on patient preferences and acceptability for emerging dosage forms within the highly diverse pediatric population poses the challenge of choosing between different formulation approaches. Therefore, given the limited availability of tailored pediatric medicines, the adjustment of products manufactured by the pharmaceutical industry for the personalization of medication in the case of specific groups of patients, such as children, as well as extemporaneous compounding, have become routine practices [4]. Unfortunately, the intervention of the pharmacist in the pharmaceutical forms prepared for adults in order to transform them into pediatric pharmaceutical forms with specific API doses, or with certain shapes or sizes, may lead to a high risk of dosing errors. Nevertheless, extemporaneous compounding is regarded as a convenient option to obtain acceptable dosage forms customized for a limited number of pediatric patients or during drug shortages. Compounded pediatric medicines are regularly available as liquid dosage forms or as powders intended for reconstitution. However, these dosage forms often have inherent limitations concerning their stability and taste.

Recently, the trend has been shifting towards replacing liquid dosage forms with solid ones due to several benefits, such as more accurate dosing, better stability, lower costs, and increasing evidence supporting better acceptability [5]. Through the collaborative efforts of the authorities and different research groups, significant progress has been made in developing age-appropriate solid formulations. In recent years, numerous innovative technologies and delivery systems with additional benefits have been proposed, but significant gaps still exist. Among them, orodispersible films (ODFs) are versatile dosage forms offering significant benefits in terms of dosing flexibility and acceptability [6]. They can be administered without water, and despite being a relatively new technology platform, several commercial products are available.

ODF manufacturing methods include solvent casting, hot-melt extrusion (HME), electrospinning, and ink printing technologies [3]. HME is a promising solvent-free technology, generally employed for APIs that display water sensitivity [7]. Moreover, an important application of HME is the preparation of amorphous solid dispersions (ASDs) from API–polymer mixtures. Their use is typically associated with improved solubility and the bioavailability of poorly soluble APIs, resulting in a faster onset of action [8]. With a better understanding of HME and amorphous systems, new technologies are continuously being explored to match individual patient needs, such as 3D printing and ODF extrusion. However, the implementation of HME involves several complex stages, and successful development requires experimental work, trained personnel [9], and significant quantities of raw materials [10,11]. Moreover, these new technologies raise concerns about the costs related to their manufacturing, as well as regulatory challenges [12]. Regarding the regulatory aspects, while some believe that a clear implementation of good manufacturing practice (GMP) and the International Organization for Standardization (ISO) is needed in order to obtain products of high and consistent quality [12], others consider that the regulatory and quality assurance for these products is comparable to that of standard magistral products [13]. Regarding the costs, it seems that personalized medicines have the potential to be cost-effective, due to the possibility of manufacturing small and versatile batches, even if they may vary widely depending on the equipment used and the country [14,15].

First applied as a sample preparation technique, Vacuum Compression Molding (VCM) is a fusion-based method used to obtain compact, HME-like samples from powders. Applying vacuum and heat, the API is melted or solubilized into a polymer, resulting in an ASD. Samples obtained via VCM are transparent discs or bars containing the amorphous form of an API incorporated in the polymeric matrix [3]. VCM was developed as a preformulation tool for quick and cost-effective ASD development, enabling the easy preparation of samples for further stability and performance testing [10]. Lately, it has been applied as a lossless processing technique to obtain small-scale formulations [10]. So far, the technique has been employed in different applications, such as the preparation of polymeric microneedles for transdermal drug delivery [16], the study of the efavirenz solubility limits in different matrix polymers [17], as a protein-stabilizing method for potential HME processing [18], or for the preparation of subcutaneous implants [19].

In pediatric therapy, there is a constant need for new preparation methods with simple working principles that deliver customized pharmaceutical products; thus, this proof-of-principle study explores the use of VCM in ODF production. The tested hypothesis is that VCM could act as a method of preparing small-scale pediatric products that is accessible to community or hospital pharmacies. The data currently available show that there is increasing interest in the introduction of personalized medicines in therapy, with one of the recurring applications being the use of this technique in clinical studies [20]. A 2021 study investigated how 3D printing technologies can be implemented in the European pharmaceutical system (i.e., the Netherlands). Of the five scenarios investigated to assess issues that could affect the implementation, industry and the patient’s homes were associated with the most challenges, while hospital pharmacies and compounding facilities were associated with the fewest [21]. Although the prospects are encouraging for manufacturing personalized medicines in hospital pharmacies and compounding facilities, there are still no international policies or guidelines to provide a framework in this respect [22]. For now, the personalized products are manufactured in accordance with the standard compounding regulations and are subject to quality, safety, and stability control to prove that they are suitable for patient administration [20].

In this study, the experimental approach focused on the plasticizer selection and API (diclofenac sodium) loading with varying ratios to yield the appropriate mechanical characteristics, disintegration, and drug release profile for the ODFs. Further investigations were performed to assess the solid-state properties. To the best of our knowledge, so far, there are no reports on VCM employed for the production of small-scale ODFs.

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Materials

The chemicals used for the preparation of the ODFs were as follows: diclofenac sodium (pharmaceutical-grade), kindly donated by Aarti Drugs Ltd. (Mumbai, India); maltodextrin with a dextrose equivalent of a maximum of 19% (Glucidex® Premium IT 19, Roquette, Lestrem, France) as a film-forming agent; sorbitol (D-Sorbitol ≥ 98%, Sigma-Aldrich, St Louis, MO, USA), xylitol (Xylisorb® 300, Roquette, Lestrem, France), and mannitol (Parteck M200, Merck, Germany) as plasticizers; and croscarmellose (Dislocel®, Mingtai Chemical Co, Ltd., Taoyuan, Taiwan) as a superdisintegrant. Commercial ODFs were purchased from community pharmacies: Melatonin Pura Fast (ESI s.p.a., Euronet Growth Milan, Italy) (Commercial Film 1, CF1) and Vitamin D3 2000 NE (IBSA Farmaceutici, Lodi, Italy) (Commercial Film 2, CF2). All other chemicals were analytical-grade.

Hales, D.; Bogdan, C.; Tefas, L.R.; Cornilă, A.; Chiver, M.-A.; Tomuță, I.; Casian, T.; Iovanov, R.; Katona, G.; Ambrus, R.; et al. Exploring Vacuum Compression Molding as a Preparation Method for Flexible-Dose Pediatric Orodispersible Films. Pharmaceuticals 2024, 17, 934. https://doi.org/10.3390/ph17070934

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